Journal Article

A chemical biology toolbox to study protein methyltransferases and epigenetic signaling

De Carvalho, Daniel D., Barsyte-Lovejoy, Dalia, Shen, Yudao, Jin, Jian, Liu, Jing, Zepeda-Velazquez, Carlos A., Lewis, Andrew M., Kaniskan, H. Ümit, McLeod, David, Vedadi, Masoud, Li, Fengling, Ackloo, Suzanne, Richardson, Paul L., Zaph, Colby, Scheer, Sebastian, Huber, Kilian V. M., Brown, Peter J., Ward, Jennifer A., Smil, David, Arrowsmith, Cheryl H., Northrop, Jeffrey P., Luo, Minkui, Medina, Tiago S., Schapira, Matthieu

2019

Overview

Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4 + T cell differentiation assays revealing the potential of individual probes to alter multiple T cell subpopulations which may have implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This chemical probe collection and associated data form a resource for the study of methylation-mediated signaling in epigenetics, inflammation and beyond. Protein methyltransferases (PMTs) are epigenetic regulatory enzymes with significant therapeutic relevance. Here the authors describe a collection of chemical inhibitors and antagonists to modulate most of the key methylation marks on histones H3 and H4, and use the collection to study of the role of PMTs in mouse and human T cell differentiation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/31 / 45/91 / 631/337/100/2285 / 631/92/458/1648 / 631/92/96 / 64/60 / 82/58 / 82/80 / 82/83 / Animals / Antagonists / Cancer immunotherapy / CD4 antigen / Cell differentiation / Cell Differentiation - drug effects / Cell Differentiation - genetics / Collection / Differentiation (biology) / Enzyme Assays - methods / Enzyme Inhibitors - pharmacology / Epigenesis, Genetic - drug effects / Epigenetics / Epigenomics - methods / HEK293 Cells / Histone-Lysine N-Methyltransferase / Histones / Histones - metabolism / Humanities and Social Sciences / Humans / Jurkat Cells / Lymphocytes / Lymphocytes T / Methylation / Methylation - drug effects / Methyltransferases - antagonists & inhibitors / Methyltransferases - metabolism / Mice, Inbred C57BL / multidisciplinary / Oncology / Organic chemistry / Probes / Protein Methyltransferases - antagonists & inhibitors / Protein Methyltransferases - metabolism / Protein Processing, Post-Translational - drug effects / Protein Processing, Post-Translational - genetics / Proteins / Reagents / Science / Science (multidisciplinary) / Selectivity / Signaling / Subpopulations / Th1 Cells - drug effects / Th1 Cells - physiology